DESCRIPTION: (Applicant's Abstract) As smoking prevalence in the United States has declined, the proportion of current smokers with concomitant psychiatric disorders has increased. Depression, anxiety disorders, and other forms of drug abuse or dependence occur in approximately 33% of cigarette smokers (Breslau, Kilbey & Andreski, 1991). This proportion is even higher in treatment populations (Hall et al, 1993; Glassman et al, 1990; Glassman, 1993). Because these individuals may have greater difficulty quitting smoking, more attention must be given to how to help them achieve smoking abstinence. The proposed study will examine the effect of pretreating smokers with the antidepressant fluoxetine before a standard, state-of-the-art smoking cessation program including cognitive-behavioral therapy and transdermal nicotine patches. [Fluoxetine was selected based on its use in prior research in smokers, its low side effect profile, and its potential to attenuate weight gain associated with cessation.] Participants will be 225 normal, healthy cigarette smokers with or without a history of Major Depressive Disorder (MDD) or current dysphoric symptoms. Participants will be randomly assigned to a treatment group: (1) placebo; (2) 20 mg fluoxetine; and (3) 40 mg fluoxetine. This randomized, placebo-controlled trial involves 14 weeks of fluoxetine (or placebo), 10 weeks of standard transdermal nicotine replacement therapy (6 weeks on 15 mg, 2 weeks on 10 mg, and 2 weeks on 5 mg nicotine patch), and 6 weeks of cognitive-behavioral group therapy with follow up visits at six weeks, eight weeks, ten weeks, three months, six months and one year after the quit date. Fluoxetine will be started four weeks before, the group therapy two weeks before, and nicotine patch on the quit date. The study will examine whether fluoxetine dose dependently improves quit rates and latency to relapse in these participants. It is expected that fluoxetine will be most efficacious in those with a history of MDD or current depressive symptoms. [Two proposed mechanism[s] for fluoxetine's effect [will] be examined: reduction of negative affect experienced [prior to and] during smoking cessation [and/or reduction of nicotine craving]. If fluoxetine safely and effectively suppresses negative affect associated with smoking cessation, a new tool will be developed to help those least likely to initiate or maintain abstinence. This could potentially save hundreds of thousands of lives each year in the United States.